Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission

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HIV-1 cell-to-cell transmission allows for 2–3 orders of magnitude more efficient viral spread than cell-free dissemination. The high local multiplicity of infection (MOI) observed at cell-cell contact sites may lower the efficacy of antiretroviral therapies (ART). Here we test the efficacy of commonly used antiretroviral inhibitors against cell-to-cell and cell-free HIV-1 transmission. We demonstrate that, while some nucleoside-analog reverse transcriptase inhibitors (NRTI) are less effective against HIV-1 cell-to-cell transmission, most non-nucleoside-analog reverse transcriptase inhibitors (NNRTI), entry inhibitors and protease inhibitors remain highly effective. Moreover, poor NRTIs become highly effective when applied in combinations explaining the effectiveness of ART in clinical settings. Investigating the underlying mechanism, we observe a strict correlation between the ability of individual drugs and combinations of drugs to interfere with HIV-1 cell-to-cell transmission, and their effectiveness against high viral MOIs. Our results suggest that the ability to suppress high viral MOI is a feature of effective ART regimens and this parameter should be considered when designing novel antiviral therapies.

Vyšlo v časopise: Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003982
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003982

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Zdroje

1. PerelsonAS, EssungerP, CaoY, VesanenM, HurleyA, et al. (1997) Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387 : 188–191.

2. GulickRM, MellorsJW, HavlirD, EronJJ, GonzalezC, et al. (1997) Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. The New England journal of medicine 337 : 734–739.

3. WalenskyRP, PaltielAD, LosinaE, MercincavageLM, SchackmanBR, et al. (2006) The survival benefits of AIDS treatment in the United States. The Journal of infectious diseases 194 : 11–19.

4. HammerSM, SquiresKE, HughesMD, GrimesJM, DemeterLM, et al. (1997) A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. The New England journal of medicine 337 : 725–733.

5. RichmanDD, MargolisDM, DelaneyM, GreeneWC, HazudaD, et al. (2009) The challenge of finding a cure for HIV infection. Science 323 : 1304–1307.

6. SattentauQ (2008) Avoiding the void: cell-to-cell spread of human viruses. Nat Rev Microbiol 6 : 815–826.

7. ZhongP, AgostoLM, MunroJB, MothesW (2013) Cell-to-cell transmission of viruses. Current opinion in virology 3 : 44–50.

8. SattentauQJ (2011) The direct passage of animal viruses between cells. Current opinion in virology 1 : 396–402.

9. DimitrovDS, WilleyRL, SatoH, ChangLJ, BlumenthalR, et al. (1993) Quantitation of human immunodeficiency virus type 1 infection kinetics. J Virol 67 : 2182–2190.

10. CarrJM, HockingH, LiP, BurrellCJ (1999) Rapid and efficient cell-to-cell transmission of human immunodeficiency virus infection from monocyte-derived macrophages to peripheral blood lymphocytes. Virology 265 : 319–329.

11. ChenP, HubnerW, SpinelliMA, ChenBK (2007) Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses. J Virol 81 : 12582–12595.

12. SourisseauM, Sol-FoulonN, PorrotF, BlanchetF, SchwartzO (2007) Inefficient human immunodeficiency virus replication in mobile lymphocytes. J Virol 81 : 1000–1012.

13. HubnerW, McNerneyGP, ChenP, DaleBM, GordonRE, et al. (2009) Quantitative 3D video microscopy of HIV transfer across T cell virological synapses. Science 323 : 1743–1747.

14. JinJ, ShererNM, HeideckerG, DerseD, MothesW (2009) Assembly of the murine leukemia virus is directed towards sites of cell-cell contact. PLoS Biol 7: e1000163.

15. IgakuraT, StinchcombeJC, GoonPK, TaylorGP, WeberJN, et al. (2003) Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299 : 1713–1716.

16. McDonaldD, WuL, BohksSM, KewalRamaniVN, UnutmazD, et al. (2003) Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 300 : 1295–1297.

17. JollyC, KashefiK, HollinsheadM, SattentauQJ (2004) HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J Exp Med 199 : 283–293.

18. RussellRA, MartinN, MitarI, JonesE, SattentauQJ (2013) Multiple proviral integration events after virological synapse-mediated HIV-1 spread. Virology 443 : 143–149.

19. Del PortilloA, TripodiJ, NajfeldV, WodarzD, LevyDN, et al. (2011) Multiploid inheritance of HIV-1 during cell-to-cell infection. Journal of virology 85 : 7169–7176.

20. ZhongP, AgostoLM, IlinskayaA, DorjbalB, TruongR, et al. (2013) Cell-to-Cell Transmission Can Overcome Multiple Donor and Target Cell Barriers Imposed on Cell-Free HIV. PloS one 8: e53138.

21. GrattonS, CheynierR, DumaurierMJ, OksenhendlerE, Wain-HobsonS (2000) Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers. Proceedings of the National Academy of Sciences of the United States of America 97 : 14566–14571.

22. JungA, MaierR, VartanianJP, BocharovG, JungV, et al. (2002) Recombination: Multiply infected spleen cells in HIV patients. Nature 418 : 144.

23. DoitshG, CavroisM, LassenKG, ZepedaO, YangZ, et al. (2010) Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 143 : 789–801.

24. CooperA, GarciaM, PetrovasC, YamamotoT, KoupRA, et al. (2013) HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature 498 : 376–379.

25. DoitshG, GallowayNL, GengX, YangZ, MonroeKM, et al. (2013) Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature In Press.

26. MonroeKM, YangZ, JohnsonJR, GengX, DoitshG, et al. (2013) IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV. Science In Press.

27. JosefssonL, PalmerS, FariaNR, LemeyP, CasazzaJ, et al. (2013) Single cell analysis of lymph node tissue from HIV-1 infected patients reveals that the majority of CD4+ T-cells contain one HIV-1 DNA molecule. PLoS pathogens 9: e1003432.

28. JosefssonL, KingMS, MakitaloB, BrannstromJ, ShaoW, et al. (2011) Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proceedings of the National Academy of Sciences of the United States of America 108 : 11199–11204.

29. RichardsonMW, CarrollRG, StremlauM, KorokhovN, HumeauLM, et al. (2008) Mode of transmission affects the sensitivity of human immunodeficiency virus type 1 to restriction by rhesus TRIM5alpha. J Virol 82 : 11117–11128.

30. AbelaIA, BerlingerL, SchanzM, ReynellL, GunthardHF, et al. (2012) Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies. PLoS pathogens 8: e1002634.

31. JollyC, BoothNJ, NeilSJ (2010) Cell-cell spread of human immunodeficiency virus type 1 overcomes tetherin/BST-2-mediated restriction in T cells. J Virol 84 : 12185–12199.

32. SigalA, KimJT, BalazsAB, DekelE, MayoA, et al. (2011) Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 477 : 95–98.

33. DuncanCJ, RussellRA, SattentauQJ (2013) High multiplicity HIV-1 cell-to-cell transmission from macrophages to CD4+ T cells limits antiretroviral efficacy. AIDS 27 : 2201–2206.

34. PermanyerM, BallanaE, RuizA, BadiaR, Riveira-MunozE, et al. (2012) Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer. Journal of virology 86 : 8773–8780.

35. MazurovD, IlinskayaA, HeideckerG, LloydP, DerseD (2010) Quantitative comparison of HTLV-1 and HIV-1 cell-to-cell infection with new replication dependent vectors. PLoS pathogens 6: e1000788.

36. TitanjiBK, Aasa-ChapmanM, PillayD, JollyC (2013) Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells. Retrovirology 10 : 161.

37. OchsenbauerC, EdmondsTG, DingH, KeeleBF, DeckerJ, et al. (2012) Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. Journal of virology 86 : 2715–2728.

38. SampahME, ShenL, JilekBL, SilicianoRF (2011) Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance. Proceedings of the National Academy of Sciences of the United States of America 108 : 7613–7618.

39. ShenL, PetersonS, SedaghatAR, McMahonMA, CallenderM, et al. (2008) Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nature medicine 14 : 762–766.

40. RookeR, TremblayM, SoudeynsH, DeStephanoL, YaoXJ, et al. (1989) Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS 3 : 411–415.

41. LarderBA, DarbyG, RichmanDD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243 : 1731–1734.

42. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. (2013). http://aidsinfonihgov/contentfiles/lvguidelines/AdultandAdolescentGLpdf: p. F1–20.

43. MeyerPR, MatsuuraSE, MianAM, SoAG, ScottWA (1999) A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Molecular cell 4 : 35–43.

44. BoyerPL, SarafianosSG, ArnoldE, HughesSH (2001) Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. Journal of virology 75 : 4832–4842.

45. ArionD, KaushikN, McCormickS, BorkowG, ParniakMA (1998) Phenotypic mechanism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry 37 : 15908–15917.

46. FengJY, LyJK, MyrickF, GoodmanD, WhiteKL, et al. (2009) The triple combination of tenofovir, emtricitabine and efavirenz shows synergistic anti-HIV-1 activity in vitro: a mechanism of action study. Retrovirology 6 : 44.

47. GotteM, ArionD, ParniakMA, WainbergMA (2000) The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. Journal of virology 74 : 3579–3585.

48. BoyerPL, SarafianosSG, ArnoldE, HughesSH (2002) The M184V mutation reduces the selective excision of zidovudine 5′-monophosphate (AZTMP) by the reverse transcriptase of human immunodeficiency virus type 1. Journal of virology 76 : 3248–3256.

49. TisdaleM, KempSD, ParryNR, LarderBA (1993) Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3′-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proceedings of the National Academy of Sciences of the United States of America 90 : 5653–5656.

50. SchinaziRF, LloydRMJr, NguyenMH, CannonDL, McMillanA, et al. (1993) Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrobial agents and chemotherapy 37 : 875–881.

51. EiseleE, SilicianoRF (2012) Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 37 : 377–388.

52. MurookaTT, DeruazM, MarangoniF, VrbanacVD, SeungE, et al. (2012) HIV-infected T cells are migratory vehicles for viral dissemination. Nature 490 : 283–287.

53. SewaldX, GonzalezDG, HabermanAM, MothesW (2012) In vivo imaging of virological synapses. Nature communications 3 : 1320.

54. ClavelF, HanceAJ (2004) HIV drug resistance. The New England journal of medicine 350 : 1023–1035.

55. AutranB, CarcelainG, LiTS, BlancC, MathezD, et al. (1997) Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277 : 112–116.

56. JilekBL, ZarrM, SampahME, RabiSA, BullenCK, et al. (2012) A quantitative basis for antiretroviral therapy for HIV-1 infection. Nature medicine 18 : 446–451.

57. RosenbloomDI, HillAL, RabiSA, SilicianoRF, NowakMA (2012) Antiretroviral dynamics determines HIV evolution and predicts therapy outcome. Nature medicine 18 : 1378–1385.

58. AdachiA, GendelmanHE, KoenigS, FolksT, WilleyR, et al. (1986) Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. Journal of virology 59 : 284–291.

59. Nowicka-SansB, GongYF, McAuliffeB, DickerI, HoHT, et al. (2012) In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrobial agents and chemotherapy 56 : 3498–3507.

60. HannaGJ, LalezariJ, HellingerJA, WohlDA, NettlesR, et al. (2011) Antiviral activity, pharmacokinetics, and safety of BMS-488043, a novel oral small-molecule HIV-1 attachment inhibitor, in HIV-1-infected subjects. Antimicrobial agents and chemotherapy 55 : 722–728.

61. LinPF, BlairW, WangT, SpicerT, GuoQ, et al. (2003) A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proceedings of the National Academy of Sciences of the United States of America 100 : 11013–11018.

62. O'DohertyU, SwiggardWJ, MalimMH (2000) Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J Virol 74 : 10074–10080.

63. Pelchen-MatthewsA, ParsonsIJ, MarshM (1993) Phorbol ester-induced downregulation of CD4 is a multistep process involving dissociation from p56lck, increased association with clathrin-coated pits, and altered endosomal sorting. The Journal of experimental medicine 178 : 1209–1222.

64. AgostoLM, YuJJ, DaiJ, KaletskyR, MonieD, et al. (2007) HIV-1 integrates into resting CD4+ T cells even at low inoculums as demonstrated with an improved assay for HIV-1 integration. Virology 368 : 60–72.

65. NettlesRE, SchurmannD, ZhuL, StonierM, HuangSP, et al. (2012) Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. The Journal of infectious diseases 206 : 1002–1011.